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Subjects

Abstract

Major depressive disorder (MDD) is a leading cause of disease burden worldwide. While the incidence, symptoms and treatment of MDD all point toward major sex differences, the molecular mechanisms underlying this sexual dimorphism remain largely unknown. Here, combining differential expression and gene coexpression network analyses, we provide a comprehensive characterization of male and female transcriptional profiles associated with MDD across six brain regions. We overlap our human profiles with those from a mouse model, chronic variable stress, and capitalize on converging pathways to define molecular and physiological mechanisms underlying the expression of stress susceptibility in males and females. Our results show a major rearrangement of transcriptional patterns in MDD, with limited overlap between males and females, an effect seen in both depressed humans and stressed mice. We identify key regulators of sex-specific gene networks underlying MDD and confirm their sex-specific impact as mediators of stress susceptibility. For example, downregulation of the female-specific hub gene Dusp6 in mouse prefrontal cortex mimicked stress susceptibility in females, but not males, by increasing ERK signaling and pyramidal neuron excitability. Such Dusp6 downregulation also recapitulated the transcriptional remodeling that occurs in prefrontal cortex of depressed females. Together our findings reveal marked sexual dimorphism at the transcriptional level in MDD and highlight the importance of studying sex-specific treatments for this disorder.

Klempan, T.A.et al.Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression. Mol. Psychiatry14, 175–189 (2009).

Acknowledgements

We thank V. Vialou for his in vivo expertise, K. Gleason at The University of Texas Southwestern Medical Center and Josée Prud'homme and Danielle Cecyre at the Douglas Bell-Canada Brain Bank for their help with procuring human brain samples, and O. Jabado for his expert advice on RNA-seq. This work was funded by National Institute of Mental Health (NIMH) grants P50MH096890 and R01MH051399 and by the Hope for Depression Research Foundation (HDRF) to E.J.N. B.L. was supported by a Frederick Banting and Charles Best postdoctoral fellowship from the Canadian Institute for Health Research (CIHR) and now by a Research Chair in Molecular Neurobiology of Mood Disorders and a Fond de Recherche du Québec-Santé (FRQ-S) Junior 1 award.

Author information

Author notes

Bin Zhang

, Li Shen

& Eric J Nestler

These authors contributed equally to this work.

Affiliations

Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Benoit Labonté

, Olivia Engmann

, Immanuel Purushothaman

, Caroline Menard

, Joseph R Scarpa

, Gregory Moy

, Yong-Hwee E Loh

, Michael Cahill

, Zachary S Lorsch

, Peter J Hamilton

, Erin S Calipari

, Georgia E Hodes

, Orna Issler

, Hope Kronman

, Madeline Pfau

, Aleksandar L J Obradovic

, Scott Russo

, Li Shen

& Eric J Nestler

Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Junshi Wang

& Yan Dong

Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Chunfeng Tan

& Carol Tamminga

Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

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Contributions

B.L. and E.J.N. conceived the project, designed the experiments and wrote the manuscript. B.L. also generated and analyzed all of the data. B.Z. and L.S. oversaw all bioinformatics analyses. A.K., Y.D., C. Tamminga, S.R., N.M. and G.T. also contributed to the study design. O.E., G.M., Z.S.L., P.J.H., E.S.C., O.I., H.K. and A.L.J.O. contributed to the cloning, in vivo surgeries and behavioral experiments. G.E.H. M.P., G.M. and A.L.J.O. contributed to the behavioral experiments. C.M., C. Tan, G.M. and M.C. helped with the protein and IHC experiments. J.W. and Y.D. generated the electrophysiological data. I.P., J.R.S., Z.S.L. and Y.-H.E.L. contributed to the differential expression and network analyses. R.L.N. packaged the viruses. C. Tamminga, N.M. and G.T. contributed brain samples. All authors contributed to the preparation of the manuscript.